1. Field of the Invention
This invention relates to pharmaceutical compositions that are useful for prevention and treatment of metabolic disorders, including insulin resistance syndromes, type 2 diabetes, weight gain, and cardiovascular disease. More specifically, the invention comprises compositions and therapeutic methods utilizing such compositions to increase insulin sensitivity.
2. Description of the Related Art
Type 2 diabetes is the most common form of diabetes, affecting many people worldwide. The disease is characterized by impaired insulin secretion and tissue insulin resistance. Insulin is produced by the Islets of Langerhans in the pancreas and regulates carbohydrate metabolism. Apart from its role in regulating carbohydrate homeostasis, insulin affects fat metabolism and liver activity. In particular, insulin affects the liver's activity in storing and releasing glucose and in processing blood lipids. Metabolic syndromes characterized by insulin resistance are usually associated with other cardiovascular risk factors including obesity, elevated plasma triglycerides, elevated plasma fibrinogen and plasminogen activator inhibitor-1, and elevated blood pressure.
Various therapies are prescribed for treatment and prevention of type 2 diabetes mellitus. The efficacy of each current therapy varies from one patient to another. Thiazoleineiones (TZD's) are one group of compounds used in the treatment of type 2 diabetes. TZD's are typically consumed orally and act as a ligand for the peroxisome proliferator-activated receptor gamma (PPARγ) located in the nucleus of adipocytes. TZD's are known for their ability to decrease insulin resistance. Examples of commercially available FDA-approved TZD's include rosiglitazone (Avandia from GlaxoSmithKline) and pioglitazone (Actos from Takeda Pharmaceuticals Company).
PPARγ agonist treatment of type 2 diabetes has many beneficial affects, including: reduced glucose levels; increased insulin sensitivity and improved β-cell function; increased HDL levels; lowered diastolic blood pressure and increased levels of the fibrinolytic plasminogen activator inhibitor-1 (PAI-1) [Zinman B. PPAR gamma agonists in type 2 diabetes: how far have we come in ‘preventing the inevitable’? A review of the metabolic effects of rosiglitazone. Diabetes Obes Metab. August 2001; 3 Suppl 1:S34-43].
Despite these beneficial affects of TZD-based therapy, many patients are either completely nonresponsive to TZD's or must supplement the therapy with insulin or insulintropic drugs. Furthermore, TZD's are known to have adverse side effects which include weight gain, edema, upper respiratory tract infection and headache [Larsen T M, Toubro S, Astrup A. PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy? Int J Obes Relat Metab Disord. February 2003; 27(2):147-161]. As such, there remains a need for therapies which would increase the percentage of patients responding to TZD's and/or decrease the side effects associated with the use of TZD's. The present invention proposes a composition and related therapy which achieves these goals.
Furthermore, the prior art in the field of diabetes treatment has been dominated by injected formulations. Specifically, the prior art is composed mainly of low-viscosity formulations intended to be injected subcutaneously. The risks associated with this approach are manifold and well known. They include repetitive injection injuries and infections.